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TABLET EVALUATION
To design tablets and later monitor tablet production
quality,quantitative evaluations and assessments of a tablet’s
chemical,physical, and bioavailability properties must be made.
NON-OFFICIAL TESTS
A. General AppearanceIts visual identity and overall “elegance,”
essential for:1) Consumer acceptance2) Control of lot-to-lot
uniformity3) Monitoring trouble-free manufacturing.
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THE CONTROL OF THE GENERAL APPEARANCE OF A TABLETINVOLVES:
I. Tablet’s sizeII. Tablet’s shapeIII. Tablet’s colorIV.
Presence or absence of an odorV. Presence or absence of a tasteVI.
Surface textureVII. Physical flawsVIII.ConsistencyIX. Legibility of
any identifying markings.
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I. SIZE AND SHAPE A compressed tablet’s are determined by the
toolingduring the compression process.
THICKNESS OF A TABLET: is the only dimensional variablerelated
to the process.
a) At a constant compressive load,tablet thickness varies with
changesin die fill, with particle sizedistribution and packing of
theparticle mix being compressed, andwith tablet weight.
b) while with a constant die fill,thickness varies with
variations incompressive load.
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NOTE:Tablet thickness is consistent batch to batch orwithin a
batch only if:
1. The tablet granulation or powder blend isadequately
consistent in particle size and sizedistribution.
2. The punch tooling is of consistent length
3. The tablet press is clean and in good working order.
Tablet thickness should be controlled within a ±5% variation
of standard value.
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MEASUREMENT OF THICKNESSA. The crown thickness of
individual tablets may bemeasured with amicrometer
1. Permits accurate measurements
2. Provides information on the variation between tablets.
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B. Other techniques involveplacing 5 or 10 tablets in aholding
tray (total crownthickness may be measuredwith a sliding caliper
scale).
Adv.: 1. more rapid than a micrometer inproviding an overall
estimate of tablet thicknessin production operations.
2. Used only if the punch and die toolingstandardizes and the
tablet machine isfunctioning properly.
Disadv.: does not as readily provideinformation on variability
between tablets.
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IMPORTANT NOTESA. Thickness control to facilitate packaging.
Problems:a) Difficulties in the use of unit dose and other
types of packaging equipment (if the volume ofthe material being
packaged is not consistent).
b) Variable thickness of tablets (relates toconsistent fill
levels of the same productcontainer with a given number of dosage
units).
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B. Weight of the tablet effected by:
i. The physical dimensions of the tabletii. Density of the
materials and their proportion.
C. The size and shape of the tablet can
influence:
1. Choice of tablet machine
2. P.S. for the granulation
3. Production lot sizes
4. Packaging operations
5. Cost to produce the tablet.
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D. The shape of the tablet alone can influence thechoice of
tablet machine used.
Ex: Shaped tablets requiring “slotted punches” must be run
atslower speeds than are possible round tablets using
conventionalpunches?Because of the nonuniform forces involved
within a tablet duringcompression
The more convex the tablet surface, the more likely it is to
causecapping problems
Forcing the use of a slower tablet machine or one
withprecompression capabilities.
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II. UNIQUE IDENTIFICATION MARKINGS. Technique: unique marking on
the tablet in addition tocolor, to aid in the rapid identification
of products(embossing , engraving, or printing).
Types of informational marking placed on atablet:
a. Company name or symbolb. Product code (e.g. National Drug
Code (NDC)
number)c. Product named. Product potency.
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III. ORGANOLEPTIC PROPERTIES.
a) Color (rapid identification and consumeracceptance).
Adv.: The color of a product must be uniform within asingle
tablet also from tablet to tablet, and from lot tolot.
Disadv.: 1- Nonuniformity (“mottling”) of color canlacks
esthetic appeal.2- Consumer can recognize nonuniformity of
contentand general poor quality of the product.
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HOW TO DISTINGUISH THE DIFFERENCE IN COLOR?A. Eye: cannot
discriminate small differences in color nor can it precisely
define
color.
Visual color comparisons against some color standard.
Color standards are subject to change with time
Frequent redefinition
Gradual and significant change in acceptable color.
B. Machines like:i. Reflectance spectrophotometryii. Tristimulus
colorimetric measurements,iii. Microreflectance photometer (measure
the color uniformity and
gloss on a tablet surface).
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b) Odor (indicate a stability problem)
Examples:
1. Odor of acetic acid (degrading aspirin tablets).
2. Odor of the drug (vitamins have a characteristicodor).
3. Added ingredients (flavoring agents havepleasant odors).
4. The dosage form (film-coated tablets usuallyhave a
characteristic odor).
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c) Taste (important in consumer acceptance ofchewable
tablets).
Many companies utilize taste panels to judge thepreference of
different flavors and flavor levels in thedevelopment of a
product.
A tablet’s level of flaws such as:
Chips, cracks, Contamination from foreign solid substances
(e.g.,hair, drops of oil, and “dirt”), surface texture (“smooth”
versus“dull”)
Method of detection:
1. Visual inspection techniques 2. Electronic devices.
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IV. HARDNESS AND FRIABILITY.Tablets require a certain amount of
strength, or hardnessand resistance to friability.
Properties:
1. Withstand mechanical shocks of handling in
manufacture,packaging, and shipping.
2. Adequate tablet hardness and resistance to powdering
andfriability are necessary requisites for consumer acceptance.
3. Relationship of hardness to tablet disintegration and
moresignificantly, to the drug dissolution release rate.
4. The monitoring of tablet hardness for drug products that
possessreal or potential bioavailability problem or that are
sensitive toaltered dissolution release profiles as a function of
thecompressive force employed.
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HARDNESS DETECTION:A. The strength of a tablet was determined by
breaking it
between the second and third fingers with the thumb actingas a
fulcrum.
If there was a “sharp” snap, the tablet was deemed to have
acceptable strength.
Tablet hardness: (tablet crushing strength) force required
tobreak a tablet in a diametric compression test.
Hardness test: a tablet is placed between anvils, and
thecrushing strength that just causes the tablet to break is
recorded.
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B. Several devices
operating to test
tablet hardness:
1. Monsanto tester
2. Strong-Cobb tester
3. Pfizer tester
4. Erweka tester
5. Schleuniger tester
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The hardness of a tablet, like its thickness, is a functionof
the die fill and compression force:
• At constant die fill, the hardness values increase
andthickness decrease as additional compression force
isapplied.
Tablet laminate or cap
Destroying the integrity of the tablet.
• At a constant compression force (fixed distancebetween upper
and lower punches
Hardness increases with increasing die fills and decreases with
lower die fills.
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GENERAL NOTES
I. Tablets are harder several hours aftercompression than they
are immediately aftercompression.
II. Lubricants can affect tablet hardness when theyare used in
too long a period.
III. Large tablets require a greater force to causefracture and
are therefore “harder” than smalltablets.
IV. For a given granulation, a flat beveled toolproduces a
tablet harder than a deep cup tool.
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V. Tablet hardness is not an absolute indicator of
strength?Since some formulations, when compressed into very hard
tablets, tendto “cap” on attrition, losing their crown
portions.
Another measure of a tablet’s strength (friability) is often
measured.
VI. Tablets that tend to powder, chip, and fragment
whenhandled
Lack elegance and consumer acceptance, and can create
excessively dirty processes in such areas of manufacturing as
coating and packaging.
Tablet’s weight variation or content uniformity problems.
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FRIABILITY• The laboratory friability tester is known as the
Roche
friabilator.
• Conventional compressed tablets that loss less than 0.5 to1.0%
of their weight are generally considered acceptable.
• Chewable tablets and most effervescent tablets (undergo
highfriability weight losses) special stack packaging.
Note: When capping is observed on friability testing (thetablet
should not be considered for commercial use, regardless ofthe
percentage of loss seen).
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FRIABILITY ADDITIONAL TESTS:
Rough handling tests usually include:
1. Vibration test
2. Drop test
3. Incline plane test
4. Shipped bottled products across the country and back again
toestimate the strength of the new tablet product in shipment.
These tests can be performed to give indication of how well
atablet will hold up in its specified package and shipping
containerduring shipment.
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OFFICIAL TESTS
A. Drug content and release.
To evaluate a tablet’s potential for efficacy:
1. The amount of drug per tablet needs to bemonitored from
tablet to tablet and batch tobatch.
2. Measure the tablet’s ability to release the drugneeds to be
ascertained.
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B. WEIGHT VARIATION. A tablet designed to contain a specific
amount ofdrug in a specific amount of tablet formula
Weight of tablet is measured to ensure that a tablet contains
the proper amount of drug.
Test: samples of tablets (usually 10) are weighted throughoutthe
compression process. The composite weight divided by 10.
Problem in the test: Within the sample that has anacceptable
average weight, there could be tablets excessivelyoverweight or
underweight.
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Note: (USP)/(NF) provides limitsfor the permissible variations
in theweights of individual tablets(expressed as a percentage of
theaverage weight of sample).
The USP variation testWeight 20 tablets individually,calculating
the average weight, andcomparing the individual tabletweights to
the average.(The tablets meet the USP test if nomore than 2 tablets
are outside thepercentage limit and no tabletdiffers by more than 2
times thepercentage limit).
Maximum Percentage Difference
allowed
Average Weight of Tablets (mg)
10130 or less
7.5130-324
5More than 324
Table: Weight Variation Tolerances for
Uncoated Tablets
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The weight variation test method determine drugcontent
uniformity of tablets if:i. All Tablets (90 to 95%) active
ingredient.ii. Uniformity of the drug distribution in the
granulation
or powder in tablets made were perfect.
Ex: Aspirin tablets (90% or more active ingredient)
±5% weight variation is close to define true potency and content
uniformity (95 to 105% of the label strength)
(if the average tablet weight is close to the theoreticaverage
weight).
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Important note: 1. The weight variation test is clearlynot
sufficient to assure uniform potency of tablets ofmoderate- or
low-dose drug (excipients make up the bulkof the tablet weight).2.
The potency of tablets is expressed in terms of grams, mg,or
micrograms (for some potent drugs) of drug per tabletand is given
as the label strength of the product.
Official compendia or other standards provide anacceptable
potency range around the label potency.i. For highly potent,
low-dose drugs such as digitoxin (not
less than 90% and not more than 110%).ii. For most of
larger-dose drugs in tablet form (not less
than 95% and not more than 105%).
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Three factors can directly contribute to contentuniformity
problems in tablets:
1. Nonuniform distribution of the drug substancethroughout the
powder mixture or granulation
2. Segregation of powder mixture or granulation during
thevarious manufacturing processes
3. Tablet weight variation.
Note:
i. The weight cannot be used as a potency indicator(except when
the active ingredient is 90 to 95% of thetotal tablet weight).
ii. In tablets with smaller dosages, good weight variationdoes
not ensure good content uniformity, (large weightvariation
precludes good content uniformity).
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Test
To assure uniform potency for tablets of low-dosedrugs, a
content uniformity test is applied.
a) 30 tablets are randomly selected for the sampleb) At least 10
of them are assayed individually (9 of 10
tablets must contain not less than 85% or more than115% of the
labeled drug content).
c) (10th tablet may not contain less than 75% or morethan 125%
of the labeled content).
d) If these condition are not met, the tablets remainingfrom the
30 must be assayed individually, and nonemay fall outside of the 85
to 115% range.
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PURITY Extraneous substances present in a raw material or a drug
that are not specifically
allowed by compendial specifications or well-defined
manufacturer’s specifications
may render the product unacceptable for
pharmaceutical use.
The purity of officialtablets is assured byutilizing raw
materials,(both active drug andexcipients)
meet official or otherrigid specifications.
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These extraneous
substances:
1. Toxic on acute orlong-term use
2. unpredictable ordeleterious effect onproduct stability
orefficacy.
Certain well-definedimpurities often appear inthe specification
of rawmaterials or drugsubstances, or if they are theproduct of
unavoidabledecomposition of the drug,they may be listed with
anupper tolerance limit.
Ex:
Aspirin tabas specifiedby the USPmaycontain nomore than0.15%
offree salicylicacidrelative tothe amountof aspirinpresent.
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C. DISINTEGRATION.For most tablets, the first important step
toward solution isbreakdown of the tablet into smaller particles or
granules, aprocess known as disintegration.
The time that it takes a tablet to disintegrate is measured in a
device described in the USP/NF.
Q/ Research has established that one should not
automaticallyexpect a correlation between disintegration and
dissolution?Since the dissolution of a drug from the fragmented
tablet control theappearance of the drug in the blood
Disintegration is a (guide for an optimum tablet formula) and
(as an in-process control test to ensure lot-to-lot
uniformity).
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COMPONENT OF DISINTEGRATION APPARATUS:
The USP device to testdisintegration:1) uses 6 glass tubes
that are 3 incheslong, open at the top
2) and held against a10-mesh screen atthe bottom end ofthe
basket rackassembly.
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Important note:To be in compliance with the USP standards, the
tablets mustdisintegrate, and all particles must pass through the
10-mesh screen intime specified.If any residue remains, it must
have a soft mass with no palpably firmcore.
Disintegration times is running for (uncoated tab., plain-coated
tab., enteric coated tab., buccal tab., and sublingualtab.).i.
Uncoated USP tablets (disintegration time 5 min (aspirin
tablets)),
but majority of the tablets have a maximum disintegration time
of30 min.
ii. Enteric coated tablets are not to disintegrate after 1 hr
insimulated gastric fluid. The same tablets are then tested
insimulated intestinal fluid and are to disintegrate in 2 hrs plus
thetime specified in the monograph.
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D. DISSOLUTION. Since disintegration testoffers no assurance
thatthe resultant particle willrelease the drug insolution at an
appropriaterate
Dissolution tests and test specifications have now developed for
nearly all
tablet products.
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Important note:A. The rate of drug absorption for acidic
drug
moieties (absorbed high in the GI tract) is determinedby (rate
of drug dissolution from tablet).
If the product objective (high peak blood levels for drug)
Obtaining rapid drug dissolution from tablet is critically
important.
The rate of dissolution may be directly related to:1. Efficacy
of the tablet product2. Bioavailability differences between
formulations.
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B. The most direct assessment of a drug’s release fromvarious
tablet formulations or products is accomplishedthrough in vivo
bioavailability measurements.
Disadvantages of in-vivo studies:
1. Length of time needed to plan, conduct and
interpretstudy.
2. Highly skilled personnel required for human studies.3. Low
precession and high variability of measurement.4. High cost of
studies.5. Use of human in ‘nonessential’ studies.6. Correlation
exist between diseased patients and the
healthy humans in the test.
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C. In vitro dissolution tests have been extensively
studied, developed, and used as an indirect
measurement of drug availability
(in preliminary assessments of formulation factors
andmanufacturing methods that are likely to
influencebioavailability).
Two objectives in the development of in vitro dissolution
testsare to show:1) The release of the drug from tablet is as close
as possible to 100%
2) The rate of drug release is uniform batch to batch and is the
sameas the release rate from those batches proven to be
bioavailableand clinically effective.
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NOTE:
• Since 1970, the United States Pharmacopeia andNational
Formulary have provided procedures fordissolution testing.
• They determine compliance with the limits ondissolution as
specified in the individualmonograph for a tablet (or capsule).
TheUSPXX/NFXV, supplement 3, specifies that either oftwo apparatus
be used for determining dissolutionrates.
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APPARATUS 1
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APPARATUS 2
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IMPORTANT NOTE
Industrial pharmacists test their formulations for
dissolution.
Their results are plotted as concentration versus time.
Values for t50% , t90%, and the percentage dissolved in30 min
are used as guides.
• The value for t50% is the length of time required for50% of
the drug to go into solution.
• A value for t90% of 30 min is an excellent goal since acommon
dissolution tolerance in USP/NF is not less than 75%dissolved in 45
min.